KR20160141045A - Pharmaceutical composition containing of Bosentan - Google Patents

Abstract

The present invention relates to a pharmaceutical composition containing bosentan and, more specifically, to a pharmaceutical composition containing bosentan, which decreases dosages by solubilizing bosentan, a poorly water soluble drug, and decreases variation in blood circulation. According to the present invention, the dosage of bosentan, a pharmaceutically allowable salt, or a solvent thereof can be reduced, so costs for manufacturing medicines and burden of patients can be reduced. In addition, a variation in an absorption amount is improved, so not only treatment effect can be increased but side effects can be reduced. An oral preparation including bosentan can be effectively manufactured.

Description

≪ Desc / Clms Page number 1 > Pharmaceutical composition containing of Bosentan &

The present invention relates to a pharmaceutical composition comprising bosentan, and more particularly, to a pharmaceutical composition containing bosentan which can reduce administration dose by solubilizing bosentan, a poorly soluble drug, .

Bocentane is represented by the general formula (1), and is represented by the general formula (1), wherein 4-tert-butyl-N- [6- (2-hydroxy-ethoxy) (EPA) as the first endothelin receptor antagonist (ERA) drug to prevent the deterioration and aggravation of exercise capacity due to pulmonary arterial hypertension, with a chemical name of pyrimidin-4-yl] 0526708 A1 and is a representative therapeutic agent for pulmonary arterial hypertension currently marketed under the trade name Tracleer tablet (Actelion). It is a drug that is administered twice a day (morning and evening) as a therapeutic agent for pulmonary arterial hypertension functional class II, III and IV patients.

Bossentan is an insoluble drug that does not dissolve in water. It dissolves 0.1mg at pH 1.0 and dissolves 0.1mg at pH 5.0. However, at pH 7.5, it has physicochemical properties requiring about 0.23 mL or more to dissolve 0.1 mg. That is, it is a drug whose solubility increases at high pH. The insolubility of these botanic drugs indicates the characteristics of high variable pharmacokinetic drugs with very large blood concentration differences depending on the patient's condition.

In addition, bosentan is a drug that needs to monitor the occurrence of hepatotoxicity during the administration period because the liver AST, ALT, and bilirubin concentrations are increased depending on the dose of the drug, that is, the blood concentration.

When the poor solubility of bosentan is improved, the dose of bosentan can be reduced, and the deviation of blood concentration of bosentan can be improved to stably monitor the occurrence of side effects. However, .

Korean Patent Laid-Open Publication No. 2008-0014002, on the other hand, discloses a technique related to the manufacture of dispersed tablets of bosentan which can be provided to patients with pulmonary arterial hypertension in children. This is a description of a formulation for ease of delivery to pediatric patients, and is different from this technique, which improves the usability only by improving the convenience of taking.

Korean Patent Publication No. 2008-0014002, February 23, 2008, claims

It is an object of the present invention to provide a novel oral bosentan formulation which is improved in poor solubility of the bosentan drug, improved bioavailability and reduced blood concentration variation.

In addition, a problem to be solved by the present invention is to provide a method for producing a novel oral formulation of bosentan that can improve the poor availability of the bosentan drug.

Hereinafter, other problems not mentioned in the above-mentioned tasks will be clearly understood by those skilled in the art from the following description.

The inventors of the present invention have found that a solubility is improved and a bioavailability is improved by applying a solid dispersion preparation technique including a polymer for solubility improvement in a bosentan which was merely developed for convenience of taking by the improvement of dispersibility One oral formulation was completed.

The bosentan controlled release oral preparation according to one embodiment of the present invention includes bosentan, a pharmaceutically acceptable salt thereof, or an active ingredient thereof as a solvate thereof, and a polymer for improving solubility.

The active ingredient may be Bosentan Monohydrate.

The polymer for improving solubility may be at least one selected from the group consisting of hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, polyethylene glycol poly (butylmethacrylate, 2-dimethylaminoethylmethacrylate, methylmethacrylate ) ≪ / RTI > copolymers.

The polymer for improving the solubility may be an amount of 0.5 to 500 parts by weight based on 100 parts by weight of the active ingredient.

The bosentan controlled release oral preparation may be a tablet.

The tablets may be either untreated or coated.

In addition, the method for preparing a bosentan oral preparation according to one embodiment of the present invention comprises dissolving bosentan, a pharmaceutically acceptable salt thereof, or a solvate thereof and a polymer for improving solubility in a solvent as an active ingredient; Solidifying the solution prepared in the preparation step; Formulation step.

According to the present invention, it is possible to reduce the dose of bosentan, a pharmaceutically acceptable salt thereof or a solvate thereof, so that it is possible to reduce the cost of manufacturing pharmaceuticals and the burden of patient's burden. In addition, it is possible to reduce the occurrence of side effects as well as the therapeutic effect by improving the deviation of the absorption amount. In addition, an oral preparation containing bosentan can be effectively produced by the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS The advantages and features of the present invention and methods of achieving them will become apparent with reference to the embodiments described in detail below with reference to the accompanying drawings. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. To fully disclose the scope of the invention to those skilled in the art, and the present invention is only defined by the claims. Unless otherwise indicated throughout the specification, 'bosentan' refers to a bosentan {4-tert-butyl-N- [6- (2-hydroxy- -Phenoxy) -2- (pyrimidin-2-yl) -pyrimidin-4-yl] -benzenesulfonamide}, a pharmaceutically acceptable salt thereof, or a solvate thereof. That is, the present invention encompasses not only bosentan but also solvate forms including salts such as bosenesulfuric acid bisulfate, bosentan maleate and the like, and hydrate forms such as bosentanil hydrate, and Bosentan Monohydrate is generally used But is not limited thereto.

[Chemical Formula 1]

The 'polymer for improving solubility' is a substance used for increasing the solubility of the main component while having a large molecular weight, and means a pharmaceutical additive. Preferably, it is a drug additive such as hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, poly Polyvinyl pyrrolidone, polyethylene glycol poly (butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer.

The term "solid dispersion" means a substance that can be obtained by simultaneously dissolving a polymer for improving the main component and solubility in a solvent, and then volatilizing the solvent. In the process of volatilizing the solvent, a pharmaceutical additive can be used as a carrier

Hereinafter, the present invention will be described in more detail.

The bosentan-controlled release oral preparation according to one embodiment of the present invention includes an active ingredient that is bosentan, a pharmaceutically acceptable salt thereof, or a solvate thereof, and preferably includes a polymer for solubility improvement By preparing a solid dispersion, the solubility of resilient bosentan can be increased.

The sustained-release base may contain 0.5 to 500 parts by weight, preferably 10 to 400 parts by weight, based on 100 parts by weight of the active ingredient. It is difficult to exhibit the poor solubility improvement effect of bosentan below the above range, and there is a risk that the emission of the main component is lowered due to the polymer when the above range is exceeded.

Due to the above-described constitution, the solubility of bosentan, which is a poorly soluble drug, can be increased. Therefore, the oral administration of bosentan according to one embodiment of the present invention can increase the bioavailability and decrease the blood concentration variation, Can be reduced.

The bosentan oral preparation can be formulated into various formulations such as powders, granules, tablets, pellets, capsules, and kits.

Preferably, the bosentan oral preparation may be a tablet, and the tablet may be a single-layer tablet, a press-coated tablet, or a multi-layer tablet.

The active ingredient contained in the oral bosentan formulation may vary depending on the patient's body weight, age, sex, and symptoms, but 32.25 mg, 62.5 mg, 125 mg, or 250 mg per day may be administered as a usual bosentan for adults. However, according to the present invention, the dose is reduced by 20% to 50% or more, thereby reducing the cost of drug manufacture and the cost of taking a patient. In addition, there is an effect of decreasing the variation of the blood concentration at the time of taking, thereby reducing the incidence of side effects as well as increasing the therapeutic effect.

The bosentan oral preparation may contain, alone or in combination with other pharmaceutically acceptable binders, excipients, disintegrants, surfactants, solubilizers, lubricants, dispersants, buffer solutions, preservatives, flavors, And can be formulated.

That is, it can be formulated into suitable forms using pharmaceutically suitable and physiologically acceptable excipients, disintegrants, sweeteners, binders, coating agents, swelling agents, lubricants, lubricants, perfumes and the like.

Examples of disintegrants include starch glycolic acid sodium, corn starch, potato starch, pregelatinized starch, bentonite, montmorillonite, veegum, microcrystalline cellulose, low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, or But are not limited to, alginic acid, croscarmellose sodium, crospovidone, sodium bicarbonate, citric acid, etc., alone or in combination.

Further, it may further include a binding agent for improving the granulation qualities and the dissolution rate of the tablet. Examples of the binder include microcrystalline cellulose, gelatin, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone (povidone), polyvinyl alcohol, copovidone, pregelatinized starch, starch, hydroxypropylcellulose And hypromellose may be used, but the present invention is not limited thereto.

It may further comprise a diluent. Examples of the diluent include, but are not limited to, starch, microcrystalline cellulose, lactose, glucose, mannitol, alkaline earth metal salts, clay, polyethylene glycol and dicalcium phosphate.

It may further comprise a lubricant. Examples of the lubricant include lubricants such as talc, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, sodium lauryl sulfate, hydrogenated vegetable oil, polyethylene glycol, glyceryl behenate, Glyceryl monostearate, and the like may be used, but the present invention is not limited thereto.

In addition, it is also possible to selectively add a solubilizing agent such as an emulsifier such as sodium lauryl sulfate, poloxamer, polysorbate and sorbitan derivatives, a surfactant, polyethylene glycol, a medium chain triglyceride, an isopropyl derivative and a pyrrolidone derivative .

Also, the components that can be included include antioxidants, colorants, flavors, preservatives, and sweeteners.

The method for preparing a Bosentan oral preparation according to one embodiment of the present invention may be carried out by dissolving the active ingredient and the polymer for improving solubility in a solvent, solidifying the prepared solution, and formulating the solution.

In the solidifying or formulating step, the granules may be prepared by directly mixing the components, by pressing them with a roller, by melt-granulating, melt congealing, extruding or the like Can be done.

In addition, the preparations of the present invention can be prepared by any suitable method in the art, for example Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA.

The matters mentioned in the above-mentioned Bosentan oral preparation and those mentioned in the above-mentioned production method are applied equally unless they are mutually contradictory.

Hereinafter, the present invention will be described in more detail with reference to Examples 1 to 9 and Experimental Example 1. The compounds used in the following Examples and Experimental Examples were the highest available in the market. Unless otherwise noted, the ingredients listed in the Handbook of Pharmaceutical Excipient were purchased and used.

< Example  1> Boscentan  Manufacture of oral preparations

1,000 T portions were prepared in the composition and content described in Example 1 of Table 1. Bocen tanil hydrate, shinetsu (Japan) is dissolved in a mixture of ethanol and methylene chloride. The colloidal silicon dioxide and crospovidone were sieved through a No. 20 sieve, mixed for 10 minutes, and placed in a fluidized bed granulator (SFC-lab, Freund, Japan). The above-prepared solution of bosentan-hypromellose was sprayed onto a fluidized bed granulator to prepare a solid dispersion granule. The solid dispersion granules were sieved through a No. 20 sieve, and then mixed with pregelatinized starch, copovidone and crospovidone for 20 minutes. Magnesium stearate sieved through a No. 35 sieve was added to the mixture and mixed for 3 minutes to prepare granules. A 9.0 mm long circular punch was mounted on a rotary tablet machine (ZPS-8, China) and tabletted to prepare tablets. Separately, Opa Dry White 03B28796 (Colorcon, Korea) was dissolved in a purified water-ethanol mixed solution to prepare a coating solution. The tablets thus completed were placed in a coater (SFC-30F, Korea) and coated with a coating solution to complete the preparation.

< Example  2> Boscentan  Manufacture of oral preparations

The procedure of Example 1 was repeated except that povidone K-25 was used in place of hypromellose as the composition and content of Example 2 in Table 1.

< Example  3> Boscentan  Manufacture of oral preparations

Except that Eudragit E100 (poly (butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate copolymer)) was used in place of hypromellose as the composition and content of Example 3 in Table 1 , And was prepared in the same manner as in Example 1.

< Example  4> Boscentan  Manufacture of oral preparations

The composition and content of Example 4 in Table 1 were prepared in the same manner as in Example 1, except that the amount of hypromellose used was increased.

Usage Ingredients Usage (mg, based on one tablet) Example 1 Example 2 Example 3 Example 4 Comparative Example 1 chief ingredient Vossen Carbohydrate 64.541 64.541 64.541 64.541 64.541 Polymer Hypromellose
(6.0 mPas) 31.25 61.25 - Povidone K-25 - 31.25 - - Eudragit E100 - - 31.25 - menstruum ethanol (300.0) (300.0) (300.0) (300.0) (300.0) menstruum Methylene chloride (300.0) (300.0) (300.0) (300.0) (300.0) Fluidizing agent Colloidal silicon dioxide 6.0 6.0 6.0 6.0 6.0 Disintegration Crospovidone 33.209 33.209 33.209 33.209 34.459 Excipient Pregelatinized starch 30.0 30.0 30.0 30.0 30.0 Binder Co-povidone 10.0 10.0 10.0 10.0 10.0 Disintegration Crospovidone 23.0 23.0 23.0 23.0 23.0 Lubricant Magnesium stearate 2.0 2.0 2.0 2.0 2.0 Coating system Opa Dry 03B28796 10.0 10.0 10.0 10.0 10.0 Coating solvent Ethanol (volatilization) (172.8) (172.8) (172.8) (172.8) (172.8) Coating solvent Purified water (volatilization) (43.2) (43.2) (43.2) (43.2) (43.2) Sum 210.0 210.0 210.0 240.0 180.0

< Comparative Example  1> Boscentan Rapid emissivity  Oral preparation ( Monolayer ) Produce

The composition and content of Comparative Example 1 in Table 1 were prepared in the same manner as in Example 1, except that hypromellose was not used and crospovidone was used.

< Experimental Example  1> Dissolution Test Results

Experiments were conducted according to the following dissolution test conditions for the oral preparation of bosentan prepared in Examples 1 and 2 and the comparative preparation for bosentan prepared in Comparative Example 1, and the results are shown in Table 2 below.

&Lt; Dissolution test conditions >

Dissolution Test Method: Dissolution Test Method 2 (paddle method) of General Test Methods of the Korean Pharmacopoeia

Paddle speed: 50 rpm

Eluent: 2nd solution (pH 6.8) of Korea Pharmacopoeia Disintegration Test Method 900 ml

Sample collection time: After 15 minutes, 30 minutes and 60 minutes after the start of the test,

Dissolution rate (%) Elution time 15 minutes 30 minutes 60 minutes Comparative Example 1 28.0 38.8 45.1 Example 1 90.8 95.1 99.8 Example 2 87.5 92.8 98.1

As shown in Table 2, Examples 1 and 2 of Oral Formulation of Bosentan showed very high solubility as compared to Comparative Example 1.

As described above, the preparation of the present invention not only increases the patient's compliance with the medication by decreasing the number of times of administration by prolonging the blood half-life and maximum blood concentration time of the drug through preparation of the solid dispersion of the active ingredient , It is possible to further reduce the possibility of side effects that may occur as a result of missing appropriate dosing times.

That is, according to the present invention, a novel bosentan oral preparation having improved bioavailability and reduced blood concentration variation by improving the solubility of the poorly soluble drug can be provided.

In addition, the present invention has been able to reduce the dose of the botanic acid drug in the treatment of pulmonary hypertension.

Claims (10)

An oral preparation comprising bosentan, a pharmaceutically acceptable salt thereof, or an active ingredient thereof as a solvate thereof, and a bosentan containing a polymer for improving solubility.
The method according to claim 1,
Orally, wherein said active ingredient is Bosentan Monohydrate.
The method according to claim 1,
The polymer for improving solubility may be at least one selected from the group consisting of hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, polyethylene glycol poly (butylmethacrylate, 2-dimethylaminoethylmethacrylate, methylmethacrylate ) &Lt; / RTI &gt; copolymers.
The method according to claim 1,
Wherein the polymer for improving the solubility is 0.5 to 500 parts by weight based on 100 parts by weight of the active ingredient.
5. The method according to any one of claims 1 to 4,
Dissolving bosentan as a active ingredient, a pharmaceutically acceptable salt thereof, or a solvate thereof and a polymer for improving solubility in a solvent;
Solidifying the solution prepared in the preparation step; And
A formulation step;
&Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof.
6. The method of claim 5,
A method for producing a bosentan oral preparation, wherein, in the step of solidifying the prepared solution, one selected from the group consisting of colloidal silicon dioxide, crospovidone, croscarmellose sodium and sodium starch glycolate is used as a carrier.
The method according to claim 6,
A process for the preparation of oral capsules of bosentan using colloidal silicon dioxide and crospovidone.
8. The method according to any one of claims 1 to 7,
Wherein the composition is a tablet.
The method of claim 3,
Wherein the polymer for improving the solubility is a hydroxamic or poly (butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate) copolymer.
The method of claim 3,
Wherein the polymer for solubility improvement is hypromellose. &Lt; RTI ID = 0.0 &gt; 21. &lt; / RTI &gt;